Large G protein α-subunit XLαs limits clathrin-mediated endocytosis and regulates tissue iron levels in vivo

Proceedings of the National Academy of Sciences of the United States of America
Qing HeMurat Bastepe

Abstract

Alterations in the activity/levels of the extralarge G protein α-subunit (XLαs) are implicated in various human disorders, such as perinatal growth retardation. Encoded by GNAS, XLαs is partly identical to the α-subunit of the stimulatory G protein (Gsα), but the cellular actions of XLαs remain poorly defined. Following an initial proteomic screen, we identified sorting nexin-9 (SNX9) and dynamins, key components of clathrin-mediated endocytosis, as binding partners of XLαs. Overexpression of XLαs in HEK293 cells inhibited internalization of transferrin, a process that depends on clathrin-mediated endocytosis, while its ablation by CRISPR/Cas9 in an osteocyte-like cell line (Ocy454) enhanced it. Similarly, primary cardiomyocytes derived from XLαs knockout (XLKO) pups showed enhanced transferrin internalization. Early postnatal XLKO mice showed a significantly higher degree of cardiac iron uptake than wild-type littermates following iron dextran injection. In XLKO neonates, iron and ferritin levels were elevated in heart and skeletal muscle, where XLαs is normally expressed abundantly. XLKO heart and skeletal muscle, as well as XLKO Ocy454 cells, showed elevated SNX9 protein levels, and siRNA-mediated knockdown of SNX9 in XLKO O...Continue Reading

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Citations

Oct 1, 2020·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Katsuhito WatanabeToshifumi Azuma
Aug 15, 2020·Current Osteoporosis Reports·Paola Divieti Pajevic
Aug 28, 2020·Investigative Ophthalmology & Visual Science·Ji Sun LeeJaya Rajaiya
Mar 20, 2018·Trends in Pharmacological Sciences·Graeme Milligan, Asuka Inoue

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